Endostatin is a 20 kDa C-terminal globular domain of the collagen-like protein (collagen XVIII) and an endogenous inhibitor of angiogenesis and tumor growth. By inhibiting endothelial proliferation, endostatin presumably keeps cancers in check by restricting the process of blood vessel formation. Recombinant human endostatin administered to mice as an unfolded suspension inhibited the growth of both human and murine tumors with no observed toxicity or drug resistance. We propose to create modified endostatin proteins that are superior to the present preparations of recombinant endostatin. The endostatin variants should have improved stability, higher potency, greater solubility, longer circulating half-lives for less frequent dosing, reduced antigenicity, and lot to lot consistency. During Phase I we will identify sites in endostatin that can be modified without significantly affecting the protein's in vitro bioactivity. During Phase II, we will manufacture sufficient quantities of the modified endostatin proteins for testing in animal models of cancer. The improved characteristics of the novel endostatin proteins will allow for the rapid validation of efficacy in both pre-clinical and clinical studies for cancer. PROPOSED COMMERCIAL APPLICATIONS: Endostatin is a natural antiangiogenic protein that inhibits the growth of cancerous human tumors in animal models. The global market for cancer therapeutics is estimated to be in excess of $6.8 billion and expected to grow every year as life expectancies increase and risk factors such as smoking remain prevalent. The modified endostatin will provide a stable, potent formation that will expedite the preclinical and clinical trials. Additional benefits for cancer patients may include less frequent dosing which will provide significant cost savings to patients and increase drug availability for the more than 9 million cancer patients in the US alone that would benefit from antiagiogenic therapy.